Novel Dimethylhydrazine-Derived Spirolactam Fluorescent

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A novel dimethylhydrazine-derived spirolactam fluorescent chemodosimeter for tracing basal ONOO- in live cells and zebrafish Caiyun Liu, Xue Zhang, Zilu Li, Yanan Chen, Zihan Zhuang, Pan Jia, Hanchuang Zhu, Yamin Yu, Baocun Zhu, and Wenlong Sheng J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.9b01298 • Publication Date (Web): 14 May 2019 Downloaded from http://pubs.acs.org on May 15, 2019

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Journal of Agricultural and Food Chemistry

A novel dimethylhydrazine-derived spirolactam fluorescent chemodosimeter for tracing basal ONOO− in live cells and zebrafish Caiyun Liu,†,* Xue Zhang,† Zilu Li,† Yanan Chen,† Zihan Zhuang,† Pan Jia,† Hanchuang Zhu,† Yamin Yu,† Baocun Zhu,†,* and Wenlong Sheng ‡,* †

School of Water Conservancy and Environment, University of Jinan, Jinan 250022,

China. ‡

Biology Institute, Qilu University of Technology (Shandong Academy of Sciences),

Jinan 250103, China. *Corresponding author. Fax: +86-531-82767617; Tel.: +86-531-82767617 E-mail address: [email protected] (C. Liu), [email protected] (B. Zhu) and [email protected] (W. Sheng)

ACS Paragon Plus Environment


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ABSTRACT 1

The precise cellular function of peroxynitrite (ONOO−) in biosystems remains

2

elusive, primarily owing to be short of ultrasensitive techniques for monitoring its

3

intracellular

4

1,2-dimethylhydrazine fluorescent chemodosimeter RDMH-PN for highly specific

5

and ultrasensitive monitoring of basal ONOO− in biosystems was rationally designed.

6

The fluorescence titration experiments demonstrated that RDMH-PN was capable of

7

quantitatively detecting 0-100 nM ONOO− (LOD = 0.68 nM). In addition,

8

RDMH-PN has the outstanding performances of ultrafast measurement, naked-eye

9

detection, and preeminent selectivity toward ONOO− to accurately detect intracellular

10

basal ONOO−. Finally, it has been confirmed that RDMH-PN not only could map the

11

intracellular basal ONOO− level by inhibit tests, but also could trace the fluctuations

12

of endogenous and exogenous ONOO− levels with diverse stimulations in live cells

13

and zebrafish.

14

KEYWORDS:

15

1,2-dimethylhydrazine; rhodamine; fluorescence bioimaging

distribution.

In

fluorescent

this

work,

a

novel

chemodosimeter;

16 17 18 19 20 21 22 23


rhodamine

peroxynitrite

B

cyclic

(ONOO−);

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24

INTRODUCTION

25

Peroxynitrite (ONOO−), an important reactive oxygen species (ROS), is formed

26

by a diffusion-limited coupling of NO and O2• − at the rate of 50-100 μM per min in

27

biological systems, and can be stable and last for hours in the nanomolar

28

concentration range.1-3 Peroxynitrite plays crucial roles in signal transduction and

29

antibacterial activities.4,5 However, growing evidence has suggested that excessively

30

produced ONOO− can damage various biomacromolecules because of its powerful

31

oxidative and nitrative capbility.6,7 An increasing number of diseases have been

32

proved to be closely associated with ONOO−, such as neurodegenerative disease,

33

chronic inflammation, and cardiovascular disorders.8-11 Unfortunately, the exact

34

cellular mechanisms of ONOO− are still not completely disclosed because of being

35

short of ultrasensitive techniques for monitoring its intracellular distribution.

36

Therefore, developing accurate and ultrasensitive methods for visualizing the ultralow

37

concentration ONOO− in the complex biosystems is urgently needed.

38

The expanding emergence of ONOO− fluorescent chemodosimeters shows their

39

extraordinary superiority in measuring exogenous and endogenous ONOO− in

40

biosystems.12-36 It is because that fluorescent chemodosimeters not only hold unique

41

imaging features of high spatiotemporal resolution, in situ detection, and

42

non-invasiveness, but also possess excellent selectivity because they are mainly

43

designed based on their specific reaction with target analytes.37-42 Up to now, available

44

ONOO− fluorescent chemodosimeters are mainly constructed based on different

45

reactive recognition moieties, including N-phenylrhodol,26-27 boronic acid pinacol

46

ester,30-34 electron-poor C=C double bond,43-49 ketoamide,50-52 hydrazine,53-58

47

organoselenium,59

48

chemodosimeters for tracing intracellular ONOO− suffer from the interferences of

and

organotellurium.60

However,


almost

all

fluorescent


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49

other ROS (e.g. H2O2 and OCl−) due to their similar properties.61-66 On the other hand,

50

most of available fluorescent chemodosimeters only detect enhanced concentration

51

intracellular ONOO− because of their low sensitivity and high reactivity, short

52

half-life, ultralow basal concentration of ONOO−. Therefore, developing specific

53

fluorescent chemodosimeters for accurately tracing intracellular basal ONOO−

54

without the interferences of other ROS remains a great challenge. In

55

this

work,

a

simple

fluorescent

chemodosimeter

employing

56

1,2-dimethylhydrazine as novel reactive recognition receptor was prepared for highly

57

specific and sensitive detection of ONOO−. Experimental results demonstrated that

58

the as-synthesized chemodosimeter not only hold prominent specificity for ONOO−

59

than other relevant species including ROS, but also can accurately detect nanomolar

60

concentration ONOO− with ultrafast response speed (< 3 s). The satisfactory

61

biocompatibility enables it to trace intracellular basal ONOO− and the fluctuations of

62

exogenous/endogenous ONOO− levels with various stimulations in live cells and

63

zebrafish. More importantly, the dimethylhydrazine-derived spirolactam has been

64

proven to be a unique model for constructing highly specific and ultrasensitive

65

chemodosimeters for ONOO−.

66

EXPERIMENTAL SECTION

67

General information. The chemicals and instrumentations are displayed in

68

Supporting Information. The fluorescence and absorption spectra were determined 1

69

minute after various species addition at 25 °C except for kinetics experiments. The

70

stock solution of chemodosimeter RDMH-PN was prepared in DMSO and the

71

adopted analytical condition is the PBS solution containing 5% DMSO (20 mM, pH =

72

7.4).

73

Preparation of chemodosimeter RDMH-PN. Phosphorus oxychloride (459 mg,


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74

3 mmol) were dissolved in absolute 1,2-dichloroethane (10 mL). Then, rhodamine B

75

(479 mg, 1 mmol) was introduced into the above mixture and refluxed for 4 hours.

76

After removing the solvent, the solution of 1,2-dimethylhydrazine dihydrochloride

77

(133 mg, 1 mmol) and DIPEA (1.349g, 10 mmol) in absolute CH2Cl2 (15 mL) was

78

added slowly to the above residue. The resulted mixture was further reacted at 25 ˚C

79

for another 12 hours. After removing CH2Cl2, the crude products were refined through

80

silica gel chromatography to afford chemodosimter RDMH-PN (296 mg, 61%).

81

1

82

3H), 3.28-3.42(m, 8H), 6.29(dd, J = 2.8, 8.8 Hz, 2H), 6.51(d, J = 2.4 Hz, 2H), 6.71(d,

83

J = 8.4 Hz, 2H), 7.30(d, J = 6.4 Hz, 1H), 7.48-7.56(m, 2H), 8.25(dd, J = 1.6, 7.2 Hz,

84

1H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 12.58, 34.60, 38.86, 44.42, 63.33, 99.10,

85

106.27, 110.03, 127.37, 127.69, 129.03, 130.09, 130.29, 132.20, 137.95, 148.55,

86

154.21, 164.10. HRMS (ESI): Calcd for C30H37N4O2 [M+H]+ 485.2911; Found,

87

485.2913.

88

RESULTS AND DISCUSSION

89

H-NMR (400 MHz, CDCl3) δ (ppm): 1.16(t, J = 7.2 Hz, 12H), 2.31(s, 3H), 2.79(s,

Design

of

chemodosimeter

RDMH-PN.

An

excellent

fluorescent

90

chemodosimeter is the perfect combination of eminent fluorophore and unique

91

reactive recognition receptor. Xanthenes have been extensively applied in exploring

92

fluorescent chemodosimeters for various target analytes owing to the outstanding

93

photophysical properties including high fluorescence quantum yield, negligible

94

cytotoxicity, and the unique easy-regulation of ring-opening of the corresponding

95

non-fluorescent spirolactam.67-69 Based on the above-mentioned description, screening

96

appropriate reactive recognition unit is essential for constructing a specific and

97

ultrasensitive ONOO− fluorescent chemodosimeters. Recently, a large number of

98

hydrazide-based fluorescent chemodosimeters have been successfully constructed for



99

identifying ONOO−.53-58 But the selectivity and reaction activity of those

100

chemodosimeters toward ONOO− are closely associated with the adopted

101

fluorophores,56,66 and especially the hydrazide-containing spirolactams are prone to be

102

hydrolyzed with the catalysis of Cu2+.67-69 Therefore, to further optimize the response

103

properties of such chemodosimeters, a novel fluorescent chemodosimeter for ONOO−

104

detection was proposed by replacing hydrazide moiety with 1,2-dimethylhydrazine

105

recognition group. Namely, the newly designed chemodosimeter was composed of

106

rhodamine B dye as fluorophore and 1,2-dimethylhydrazine as the reactive unit

107

(RDMH-PN, Scheme 1 and 2). The 1,2-dimethylhydrazine group was integrated into

108

fluorophore, which formed spirocyclic ring system to reduce the fluorescence. Upon

109

the addition of ONOO−, chemodosimeter RDMH-PN causes the ring-opening

110

reaction, and leads to the recovery of fluorescence.61-65 The design and reaction

111

mechanism has been also verified by HPLC and HRMS (Fig. S1-S2).

112 113

Scheme 1. Recognition mechanism of chemodosimter RDMH-PN for ONOO−

114

detection.

115 116

Scheme 2. Preparation of chemodosimter RDMH-PN.

117

Determination of ONOO−. Firstly, fluorescence spectra of RDMH-PN with

118

ONOO− were obtained in the PBS solution (20 mM, pH 7.4, 5% DMSO). As depicted

119

in Figure 1a, chemodosimeter RDMH-PN solution emitted negligible fluorescence.


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120

As designed, the emission peak was enhanced gradually with ONOO− (0-10 μM).

121

Satisfactorily, increasing ONOO− concentrations (1-10 μM) manifest a linear

122

enhancement of the RDMH-PN fluorescence intensity (linear equation: y = 286942 ×

123

[ONOO−] (μM) + 235185, R2 = 0.9907) (Figure 1b). Furthermore, to estimate the

124

capability of RDMH-PN to detect extremely low concentration ONOO−, the

125

additional titration of ONOO− in the range of ultralow concentration was implemented.

126

Excitedly, the favorable linear dependence between fluorescence intensities and

127

ONOO− concentrations ranging from 0-100 nM was also obtained, demonstrating

128

chemodosimeter RDMH-PN could accurately determine ONOO− at the nanomolar

129

level (Figure 1c). Subsequently, the limit of detection was determined to be 0.68 nM

130

(3σ/k). Furthermore, the ultrafast reaction (< 3 s) between RDMH-PN and 1 equiv.

131

ONOO− has been confirmed in Figure 2. These spectral studies revealed that

132

chemodosimeter RDMH-PN has powerful capability to implement the real-time

133

determination of highly reactive ONOO− with excellent sensitivity (Table S1).

134



135 136

Figure 1. (a) Concentration-dependent fluorescent spectra of RDMH-PN (5 μM) with

137

different concentration ONOO− (0-10 μM) under the PBS solution (20 mM, pH = 7.4,

138

5% DMSO). (b) The linear dependence between fluorescence intensities and ONOO−

139

concentrations (1-10 μM). (c) The linear dependence between fluorescence intensities

140

and ONOO− concentrations (0-100 nM). λex = 520 nm. Slit widths: Wex = Wem = 3 nm.

141

The spectra were recorded in 1 min after ONOO− injection at 25 °C.

142 143

Figure 2. Time-course of RDMH-PN (5 μM) with ONOO− (5 μM) under the PBS

144

solution (20 mM, pH = 7.4, 5% DMSO). λex = 520 nm, λem = 585 nm. Slit widths: Wex

145

= Wem = 3 nm. This experiment was performed at 25 °C.

146

The absorption spectrum of chemodosimter RDMH-PN for determining ONOO−

147

was also estimated in the PBS solution (20 mM, pH 7.4, 5% DMSO). Chemodosimter

148

RDMH-PN (5 μM) displayed negligible absorption intensity before reacting with

149

ONOO−. As predicted, the reaction between chemodosimter RDMH-PN and ONOO−


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150

led to clear enhancement of absorption intensity at 570 nm. Color change of

151

RDMH-PN could be distinctly observed with and without ONOO−, which was

152

beneficial to naked-eye observation.

153 154

Figure 3. Absorption spectra of RDMH-PN (5 μM) with/without ONOO− (5 μM)

155

under the PBS solution (20 mM, pH = 7.4, 5% DMSO). Inset: photos of the

156

RDMH-PN (20 μM) solution with/without ONOO− (20 μM). The spectra were

157

recorded in 1 min after ONOO− injection at 25 °C.

158

These results manifested the usability of chemodosimter RDMH-PN as an

159

ultrafast quantitative tool for monitoring ONOO− at ultralow concentration level

160

under physiological conditions. The above-mentioned recognition properties of

161

RDMH-PN make it convenient to trace intracellular basal ONOO−.

162

Specificity of chemodosimeter RDMH-PN toward ONOO−. The specificity of

163

RDMH-PN has been verified in the presence of ONOO− and other relevant analytes

164

including K+, Na+, Ca2+, Mg2+, Cu2+, Cu+, Fe2+, Fe3+, Zn2+, Br−, SO32−, CO32−, NO3−,

165

NO2−, NO, TBHP, H2O2, •OtBu, •OH, O2−, 1O2, Cys, Hcy, GSH, OCl−, and ONOO−.



166

As shown in Figure 4, only ONOO− induced a significant increment of fluorescence

167

intensity at 585 nm, and other analytes could not cause the obvious changes of

168

fluorescence intensity. Subsequently, the possible interferences of pH on

169

chemodosimeter RDMH-PN for monitoring ONOO− were also studied. These results

170

manifested that chemodosimeter RDMH-PN possessed a satisfactory stability and

171

response capability for ONOO− in the physiological pH ranges (Fig. S3). Moreover,

172

the eminent photo-stability of chemodosimeter RDMH-PN was further proven (Fig.

173

S4). The above consequences implied chemodosimeter RDMH-PN could accurately

174

trace intracellular ONOO− in the bioimaging applications.

175 176

Figure 4. Fluorescence changes of RDMH-PN (5 μM) with various species (100 μM

177

except for annotations) under the PBS solution (20 mM, pH = 7.4, 5% DMSO). 1.

178

Blank, 2. K+ (1 mM), 3. Na+ (1 mM), 4. Ca2+ (1 mM), 5. Mg2+ (1 mM), 6. Cu2+, 7.

179

Cu+, 8. Fe2+, 9. Fe3+, 10. Zn2+, 11. Br−, 12. SO32−, 13. CO32−, 14. NO3−, 15. NO2−, 16.

180

NO, 17. TBHP, 18. H2O2 (500 μM), 19. •OtBu, 20. •OH, 21. O2−, 22. 1O2, 23. Cys (500

181

μM), 24. Hcy (500 μM), 25. GSH (1 mM), 26. OCl−, and 27. ONOO− (5 μM). λex =


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182

520 nm, λem = 585 nm. Slit widths: Wex = Wem = 3 nm. The spectra were recorded in 1

183

min after analytes injection at 25 °C.

184

Bioimaging of ONOO− in live cells. To study the recognition properties of

185

chemodosimeter RDMH-PN for ONOO− in complex living systems, we conducted

186

biological imaging experiments with RAW 264.7 macrophages. Initially, we checked

187

the cytotoxicity of chemodosimeter RDMH-PN by a cell counting kit-8 (CCK-8)

188

method. These results displayed chemodosimeter RDMH-PN had negligible effect on

189

cell survival (Figure 5). Then, we followed to test whether chemodosimeter

190

RDMH-PN has capability to trace intracellular basal ONOO−. Firstly, the bioimaging

191

of control cells was carried out, and almost no intracellular fluorescence was observed

192

(Figure 6a-c). As predicted, the macrophages preincubated with chemodosimeter

193

RDMH-PN for 30 minutes exhibited the obvious red intracellular fluorescence under

194

the same bioimaging conditions (Figure 6d-f). Additionally, the macrophages

195

pretreated with 4-amino-tempo (a superoxide scavenger, it causes the reduction of

196

intracellular ONOO− levels) was further treated with chemodosimeter RDMH-PN for

197

30 minutes, and the weaker red intracellular fluorescence than the control

198

macrophages incubated with only RDMH-PN was observed (Fig. S5). These data

199

demonstrated chemodosimeter RDMH-PN was quite sensitive to basal ONOO− in

200

normal macrophages without extrinsic stimuli. Subsequently, the macrophages

201

preincubated with chemodosimeter RDMH-PN for 30 minutes were further treated

202

with ONOO− (20 µM) for another 20 minutes, and the stronger intracellular

203

fluorescence was successfully obtained (Figure 6g-i), demonstrating chemodosimeter



204

RDMH-PN could determine the changes of exogenous ONOO− concentrations. To

205

estimate the capability of RDMH-PN in detecting endogenous ONOO−, the

206

macrophages were stimulated by PMA (1.0 µg/mL) and LPS (1.0 µg/mL) for 30

207

minutes. With extending incubation with RDMH-PN for another 20 minutes, a

208

significant increase of intracellular fluorescence has been observed (Figure 6j-l).

209

Above results demonstrated that chemodosimeter RDMH-PN could map the basal

210

ONOO− and the changes of endogenous/exogenous ONOO− concentrations in live

211

macrophages effectively (Figure 6m).

212 213

Figure 5. Macrophage viability with different concentration chemodosimeter

214

RDMH-PN.

215 216

Figure 6. Fluorescence images of live macrophages: (a-c) control cells; (d-f) cells

217

treated with RDMH-PN; (g-i) cells preincubated with RDMH-PN, and then treated


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218

with ONOO−; (j-l) cells preincubated with LPS and PMA, and then incubated

219

RDMH-PN; (m) the fluorescence intensities of the corresponding cells.

220

Bioimaging of ONOO− in zebrafish. With the favorable bioimaging

221

performance of RDMH-PN in live cells, we then examined whether it has the

222

possibility to bioimage ONOO− in vivo. Based on this consideration, the 4-day-old

223

zebrafish was chosen as a suitable organism model to visualize basal ONOO− and the

224

changes of endogenous/exogenous ONOO− concentrations in our experiments (Figure

225

7). Firstly, the bioimaging of control zebrafish was carried out, and almost no

226

fluorescence was observed (Figure 7a-c). As designed, the zebrafish preincubated

227

with chemodosimeter RDMH-PN for 30 minutes exhibited the obvious red

228

fluorescence under the same bioimaging conditions (Figure 7d-f). These results

229

indicated chemodosimeter RDMH-PN was very sensitive to basal ONOO− in normal

230

zebrafish without extrinsic stimuli. Subsequently, the zebrafish preincubated with

231

chemodosimeter RDMH-PN for 30 minutes was further treated with ONOO− (50 µM)

232

for another 20 minutes, and the stronger red fluorescence was also successfully

233

obtained (Figure 7g-i), demonstrating chemodosimeter RDMH-PN could monitor the

234

changes of exogenous ONOO− levels in vivo. Moreover, to estimate the capability of

235

RDMH-PN in detecting endogenous ONOO− in vivo, the zebrafish were stimulated

236

by PMA (1.0 µg/mL) and LPS (1.0 µg/mL) for 30 minutes. With extending incubation

237

with RDMH-PN for another 20 minutes, the significant increase of fluorescence also

238

confirmed the bioimaging applicability in vivo (Figure 7j-l). Taking all these results in

239

consideration, it can be concluded that chemodosimeter RDMH-PN was able to



monitor

intracellular

basal

ONOO−

240

accurately

and

241

endogenous/exogenous ONOO− concentrations in zebrafish.

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the

changes

of

242 243

Figure 7. Fluorescence images of zebrafish: (a-c) control zebrafish; (d-f) zebrafish

244

treated with RDMH-PN; (g-i) zebrafish preincubated with RDMH-PN, and then

245

treated with ONOO−; (j-l) zebrafish preincubated with LPS and PMA, and then

246

incubated RDMH-PN.

247

In conclusion, we have constructed a novel fluorescent chemodosimeter for

248

tracing intracellular basal ONOO− in biosystems. The high specificity and

249

ultrasensitivity of chemodosimeter RDMH-PN was ascribed to the adoption of

250

reactive recognition group of 1,2-dimethylhydrazine. Bioimaging applications of

251

chemodosimeter RDMH-PN in tracing intracellular basal ONOO− and the changes of

252

ONOO− concentrations with different stimulations in live cells and zebrafish were

253

confirmed. Therefore, we anticipate that chemodosimeter RDMH-PN may be used as

254

a powerful tool to explore the generation and transport of ONOO− in biosystems.

255

Moreover, the 1,2-dimethylhydrazine modified spirocyclic structure has been proven

256

to be a unique model for constructing highly specific and ultrasensitive

257

chemodosimeters for ONOO− detection.


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258

ASSOCIATED CONTENT

259

*Supporting Information

260

The Supporting Information is available free of charge on the ACS Publications

261

website at DOI: 10.1021/acs.jafc.×××××××.

262

Experimental methods and additional data.

263

Notes

264

The authors declare no competing financial interest.

265

ACKNOWLEDGEMENTS This study was financially supported by NSFC (21777053 and 21607053) and

266 267

Shandong Provincial Natural Science Foundation (ZR2017MB014).

268

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